The present invention relates to apparatus and methods for medical imaging, specifically to the use of passive markers for magnetic resonance imaging. In a particular, the invention relates to the use of fluorine-19 (19F) nuclei containing compounds as contrast agents and markers for medical devices used in interventional magnetic resonance angiography.
Currently, x-ray fluoroscopy is the preferred imaging modality for cardiovascular interventional procedures. No other method, at this time, has the temporal or spatial resolution of fluoroscopy. As good as fluoroscopy is, however, it does have drawbacks. Catheterization is required in order to directly inject the high concentration of iodinated contrast agent required. Systemic administration of the contrast agent would require too high a dose of agent. Additionally, iodinated contrast agents are nephrotoxic with a real incidence of acute renal failure, particularly in patients with compromised renal function. Allergic reactivity also serves as a contraindication for certain patients. Visualization and tracking of devices under fluoroscopy is accomplished either by the device""s inherent adsorption of x-rays, or by the placement of radiopaque markers. Fluoroscopy generates a compressed, two dimensional image of what are three dimensional structures. This requires multiple views to appraise complex vasculature. Moreover, fluoroscopy uses ionizing x-ray radiation with its attendant hazards. This is an issue for the patient during protracted or repeated interventions. It is a daily issue for the interventionalist who must also cope with the burden of personal dose monitoring and wearing lead shielding.
One imaging modality, which has the potential to supplant fluoroscopy, or perhaps replace it in the long term, is magnetic resonance imaging (MRI). MRI does not use ionizing radiation and does not require catheterization to image vasculature. MRI contrast agents, which are often necessary for best resolution, are much less nephrotoxic than iodinated fluoroscopy agents and are effective when administered intravenously.
One advantage of MRI is that different scanning planes and slice thicknesses can be selected without loss of resolution. This selection permits high quality transverse, coronal and sagittal images to be obtained directly. MRI has greater soft tissue contrast and tissue discrimination than computed tomography (CT) or other x-ray based imaging modalities, such as angiography. The reason for this being that in CT, the x-ray attenuation of tissues determines image contrast, whereas in MRI at least four separate variables can determine MRI signal intensity: (i) spin-lattice (longitudinal) relaxation timexe2x80x94T1, (ii) spin-spin (transverse) relaxation timexe2x80x94T2, (iii) proton density, and (iv) flow. MRI is presently used for diagnostic applications, but interventional magnetic resonance (iMR) angiography is an active area of research. For example, MRI guided balloon angioplasty has been performed to demonstrate feasibility. Similarly, stent placement in humans under MRI has also been demonstrated.
The technique of MRI encompasses the detection of certain atomic nuclei (those possessing magnetic dipole moments) utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to x-ray computed tomography in providing a cross-sectional display of the body organ anatomy, only with excellent resolution of soft tissue detail. In its current use, the images constitute a distribution map of protons, and their properties, in organs and tissues. However, unlike x-ray computer tomography, MRI does not use ionizing radiation. The fundamental lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. Additionally, any scan plane can readily be selected, including transverse, coronal, and sagittal sections. MRI is, therefore, a safe non-invasive technique for medical imaging.
The hydrogen atom, having a nucleus consisting of a single unpaired proton, has one of the strongest magnetic dipole moments of nuclei found in biological tissues. Since hydrogen occurs in both water and lipids, it is abundant in the human body. Therefore, MRI is most commonly used to produce images based upon the distribution density of protons and/or the relaxation times of protons in organs and tissues. Other nuclei having a net magnetic dipole moment also exhibit a nuclear magnetic resonance phenomenon which may be used in MRI applications. Such nuclei include carbon-13 (six protons and seven neutrons), fluorine-19 (9 protons and 10 neutrons), sodium-23 (11 protons and 12 neutrons), and phosphorus-31 (15 protons and 16 neutrons).
Fluoroscopy uses contrast agents to enhance the imaging of otherwise radiolucent tissues. Not surprisingly, fluoroscopic contrast agents work by x-ray absorption. Contrast agents also exist for MRI image enhancement. They work in a different manner, and typically shorten either the T1 or T2 proton relaxation times, giving rise to intensity enhancement in appropriately weighted images. The most popular MRI contrast materials are T1 shortening agents and, in general, paramagnetic ions of elements with an atomic number of 21 to 29, 42 to 44 and 58 to 70 have been found effective as MRI contrasting agents. Such suitable ions include chromium(III), manganese(II), iron(III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium(III), neodymium(III), samarium(1II) and ytterbium(III). Because of their very strong magnetic moments, gadolinium(III), terbium(III), dysprosium(III), holmium(III) and erbium(III) are preferred. Gadolinium(III) ions have been particularly preferred as MRI contrast agents.
In an MRI experiment, the nuclei under study in a sample (e.g. protons, 19F, etc.) are irradiated with the appropriate radio-frequency (RF) energy in a controlled gradient magnetic field. These nuclei, as they relax, subsequently emit RF energy at a sharp resonance frequency. The resonance frequency of the nuclei depends on the applied magnetic field. In some cases, the concentration of nuclei to be measured is not sufficiently high to produce a detectable magnetic resonance signal. Signal sensitivity may be improved by administering higher concentrations of the target nuclei or by coupling the nuclei to a suitable xe2x80x9cprobexe2x80x9d which will concentrate in the body tissues of interest.
As noted above, iMR angiography is an active area of research. Device tracking and visualization under MRI is necessary for MRI guided interventions. Plastic devices show up poorly under MRI. The reason is that even though the majority of polymers contain hydrogen nuclei, the resonance signals from protons in polymers are broad and chemically shifted from protons in water from which the majority of the MRI signal is derived. Polymeric catheters, for example, show up as regions of little or no signal under MRI (signal voids). Hence, there is a need for markers to track and visualize interventional devices.
MRI markers are divided into two categories, active and passive. Active markers, as the name implies, participate in the radio frequency signal transmission or reception of the scanner. This includes markers that emit an RF signal, markers that receive an RF signal and convey it to the scanner via a connection, and markers that generate their own magnetic or electrical field by application of electrical currents. The term active implies some sort of electrical circuit is involved. Conversely, passive markers use no wires or circuitry and work by several mechanisms. One scheme is to distort the magnetic field of the scanner. Another is by enhancing or modifying the signal from protons in the vicinity. Still another is by containing nuclei with their own distinct signal that is different from water or fat. Passive markers have the advantage that they are simpler and, generally, have fewer parts. They require no connection to the scanner or additional circuitry. There also may be the perception amongst physicians that active currents and voltages in or on interventional devices create additional safety issues to be managed. Lastly, passive markers are conceptually similar to the radiopaque markers in fluoroscopy, even if they work in a very different way.
There are two main types of passive markers being proposed. One is based on magnetic susceptibility. This usually includes paramagnetic or ferromagnetic particles, bands, or other components placed in or on the device. These materials perturb the magnetic field in the vicinity of the device. This alters the resonance condition of protons in the vicinity. The net result is a signal void that appears black in MRI images.
The second scheme uses the currently approved gadolinium contrast agents; however, the contrast agents are placed inside the device. For example, gadolinium contrast solution is used to fill the lumen of a catheter or inflate an angioplasty balloon. In T1 weighted images, aqueous solutions of gadolinium show a signal enhancement due to the T1 shortening effect of the gadolinium. Gadolinium also shortens T2 and gives some enhancement in those images as well. In contrast to the susceptibility artifact which is dark, an aqueous gadolinium solution marker shows up bright.
Another mechanism is possible if the medical device contains nuclei other than protons. In this case, it is possible to track the device due to the distinctive signal of this other nuclei, especially its frequency. Protons, hydrogen nuclei, have the advantage that they are abundant and have very good MRI sensitivity. They also have only two allowed spin states (nuclear spin=xc2xd). Nuclei with a spin greater than xc2xd have a quadrapole dipole moment, which broadens their NMR resonance signal. Fluorine-19 has reasonable sensitivity compared to 1H and a resonant frequency that can be accommodated by the RF equipment in current scanners. Fluorine-19 also has a spin quantum number of xc2xd, like hydrogen nuclei, giving it a sharp NMR signal.
What has been needed, and heretofore unavailable, in the art of interventional magnetic resonance angiography are medical devices (such as guidewires, catheters and implantable prostheses, e.g., stents) which contain passive markers for visualization under MRI. Such medical devices should provide a visible indication of the device during iMR angiography, without reliance upon susceptibility artifacts and signal voids. The present invention satisfies these and other needs.
Briefly, and in general terms, the present invention is directed to the design and configuration of medical devices for use in interventional magnetic resonance (iMR) angiography. The medical devices of the present invention incorporate compounds that contain fluorine-19 (19F) nuclei for use as contrast agents and passive markers. MRI guided balloon angioplasty has been performed to demonstrate feasibility. Similarly, stent placement in humans under MRI has also been demonstrated. Configuration of such medical devices with 19F markers will enhance the viability of iMR angiography. Since the art of iMR angiography has relied on the use of gadolinium contrast agents and signal voids as passive markers, the use of contrast agents and markers containing fluorine-19 material provides a new and useful way for MRI.
A fluorine-19 containing marker may be used on any medical device which may benefit from enhanced MRI visibility. The fluorine marker of the device may encompass the device partially or wholly, meaning that the entire device may be partially, or wholly, constructed of a fluorine containing material. In addition, there may be more than one marker on the device. The device may be a guidewire, guiding catheter, angioplasty catheter, stent, embolic protection device, endovascular graft, endotracheal tube, Foley catheter, Hickman catheter, Broviac catheter, cerebrospinal fluid shunt, biliary stent, stylet, biopsy needle, electrode, percutaneous or endoluminal transducer or other desired interventional medical device. It may be a temporary or permanently implanted device. There are no limitations on the size, diameter, length or other materials of the device other than they must be MRI safe. The fluorine-19 material may be configured from an elastomer, a fluid, a fluorosilicone, or a perfluorocarbon grease or oil. It is advantageous that the fluorine-19 be incorporated in a physical form that is in a fluid, mobile state at the molecular level. This gives the fluorine-19 a sharp nuclear magnetic resonance signal. Such materials may be incorporated into marker bands and/or stripes, or may be deposited into or dispersed within the walls or lumens of the medical device to be visualized under interventional magnetic resonance angiography.
In one embodiment, a medical device including the present invention may be in the form of a balloon catheter assembly having a catheter tube having wall, an outer surface, a proximal end portion and a distal end portion. The device may further include an expandable member (balloon) associated with the distal end portion of the catheter and one more markers formed from fluorine-19 containing material. The markers may be in the form of a band or stripe formed within or disposed on the wall of the catheter. Similarly, a stent incorporating fluorine-19 containing material may be disposed on the balloon. In addition, fluorine-19 markers may be incorporated into endovascular grafts and embolic protection devices.
The use of fluorine-19 containing markers and contrast agents provides a novel method of performing angioplasty using magnetic resonance imaging. Such a method includes providing a catheter assembly including a catheter tube having an expandable member (balloon) formed on the distal end portion of the catheter and at least one marker having fluorine-19 containing material formed on the catheter tube and positioned proximate the expandable member. The distal end of the catheter is advanced to a desired location in a patient vasculature having a stenosis or other lesion. The vasculature, stenosis and the fluorine-19 containing material are visualized through magnetic resonance angiography. The balloon is inflated so as to expand the stenosis and open the vasculature, then the expandable member is contracted and the catheter and the expandable member are withdrawn from the patient vasculature. A stent mounted on a balloon catheter may be deployed in a similar manner.